CN100475132C - Implantable electrode system, method and device for measuring the concentration of an analyte in a human or animal body - Google Patents
Implantable electrode system, method and device for measuring the concentration of an analyte in a human or animal body Download PDFInfo
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- CN100475132C CN100475132C CNB2006101484619A CN200610148461A CN100475132C CN 100475132 C CN100475132 C CN 100475132C CN B2006101484619 A CNB2006101484619 A CN B2006101484619A CN 200610148461 A CN200610148461 A CN 200610148461A CN 100475132 C CN100475132 C CN 100475132C
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
Abstract
An electrode system for determining an analyte concentration in a human or animal may comprise first and second electrodes. The first electrode may be configured to produce a first signal from which the analyte concentration can be determined, and may have a first measuring sensitivity that is optimized for a first analyte concentration range. The second electrode may be configured to produce a second signal from which the analyte concentration can be determined, and may have a second measuring sensitivity that is optimized for a second analyte concentration range that is different from the first analyte concentration range. An analytical unit may be configured to determine the analyte concentration based on the first signal if the analyte concentration falls within the first analyte concentration range, and to determine the analyte concentration based on the second signal if the analyte concentration falls within the second analyte concentration range.
Description
Technical field
The present invention relates to be used to measure the implantable electrode system of human body or the intravital analyte concentration of animal, equipment and corresponding method with such electrode system.For example understand such electrode system by US6175752B1.
Background technology
The measurement of the physiology analyte of interest of for example lactate that the implantable electrode system permission will be carried out in patient's body and glucose and so on.Compare with the sample of taking-up body fluid in body and in the external conventional procedure of analyzing, it is relevant with important advantage that this class is in vivo measured, and specifically, described advantage is the feasibility of the automatic continuous detecting of measured value.
But, the related following shortcoming of known implant: determining analyte concentration under traditional situation of in vitro analyzing feasible lower precision and reliability than adopting only.
In order to improve certainty of measurement, US2005/0059871A1 proposes to adopt simultaneously the analyte concentration that a plurality of electrode measurements are paid close attention to and analyzes the measuring-signal that obtains by calculating mean value.Measure as additional, suggestion adopts additional sensor to determine other analyte concentration or physiological parameter, and carries out likelihood's test of each result by the concentration of so various analytes of determining.
Although obtained improvement by this way, but, adopt the known electrodes system to measure the intravital concentration of glucose of diabetics with enough accuracy, remain infeasible so that send with needing the patient and take the relevant fully reliable alarm of extremely low or high concentration of glucose of the precautionary measures.
Summary of the invention
Therefore, the objective of the invention is to propose a kind of being used in the mode of high-acruracy survey human body or the intravital analyte concentration of animal more.
This purpose realizes by the implantable electrode system that is used to measure human body or the intravital analyte concentration of animal, described implantable electrode system comprises first and second measurement electrode of the measuring-signal that is used for the relevant information of definite each analyte concentration self-contained with to be measured, first measurement electrode has the first measurement sensitivity of first concentration range of suitable analyte in view of the above, and second measurement electrode has the second measurement sensitivity of second concentration range of and suitable analyte different with the first measurement sensitivity.
This purpose also realizes by a kind of equipment that is used to measure human body or the intravital analyte concentration of animal, described equipment comprises the electrode system of described type, be connected to the analytic unit that electrode system is used to analyze the measuring-signal of first and second measurement electrode, and wherein stored at least one first sensitivity parameter of the measurement sensitivity that characterizes first measurement electrode and characterized the memorizer of at least one second sensitivity parameter of the measurement sensitivity of second measurement electrode, analytic unit is designed allow to determine which concentration range analyte concentration belongs to so that analyze one of them the step of at least one measuring-signal of two measurement electrode in view of the above, if and analyte concentration belongs to first concentration range, then analyze the measuring-signal of first measurement electrode so that determine analyte concentration by first sensitivity parameter, if and analyte concentration belongs to second concentration range, then analyze the measuring-signal of second measurement electrode so that determine analyte concentration by second sensitivity parameter.
In such equipment, the concentration range of measurement electrode can be overlapping.Even the concentration range that can make a measurement electrode become within the obviously bigger concentration range that is included in another measurement electrode fully part among a small circle.Therefore, possible situation is, for example, the measuring-signal of first measurement electrode is by successive analysis, the measuring-signal of second measurement electrode then only first measuring-signal the analysis showed that analyte concentration belongs to the concentration range of second measurement electrode time just analyzed.
This purpose also realizes by the method for implantable electrode system measurement human body or the intravital analyte concentration of animal by a kind of being used for, second measurement electrode that described implantable electrode system comprises first measurement electrode with first measurement sensitivity and has the second measurement sensitivity that is different from the first measurement sensitivity, the analyte concentration that belongs to first concentration range in view of the above determines by the measuring-signal of analyzing first measurement electrode, and the analyte concentration that belongs to second concentration range is determined by the measuring-signal of analyzing second measurement electrode.
In the context of the present invention, the analyte concentration that can recognize acute variation in human body or the animal body can't adopt single measurement electrode to determine under the unconfined situation of certainty of measurement.Normally because the measuring range of selected measurement electrode is big more, then the measurement sensitivity at low concentration place is low more for this.But not to design measurement electrode by the optimal compromise of making great efforts to obtain between maximum possible measuring range and the highest energy measurement sensitivity, but, obtain wide-measuring range by adopting a plurality of measurement electrode that cover the different measuring scope and therefore have different measuring sensitivity according to the present invention.The measurement sensitivity of the measurement sensitivity by first measurement electrode optimized at first concentration range and second measurement electrode optimized at second concentration range can realize bigger measuring range under the situation of certainty of measurement without limits.
Therefore, utilization is according to electrode system of the present invention, analyte concentration can adopt the measurement electrode that has favourable measurement sensitivity for the respective concentration scope to measure all the time, and no matter near the analyte concentration the measurement electrode is higher or lower with respect to specified or average biological value.In this way, can obtain the remarkable improvement of certainty of measurement for the measuring range of any size.
Because the obvious improvement of certainty of measurement can adopt electrode system according to the present invention to obtain, the statistical analysis of measuring-signal that does not for example therefore need each measurement electrode of implementing according to prior art is so that can adopt more easy means according to the present invention to obtain higher certainty of measurement.But, a plurality of first measurement electrode are used for the upper concentration range and a plurality of second measurement electrode are used for the lower concentration range so that the reduction system further improves certainty of measurement to interferential sensitivity or by statistical analysis, obviously be feasible.
If a plurality of first or a plurality of second measurement electrode be used for electrode system, then be used to improve each measurement electrode that the statistical analysis of certainty of measurement need be triggered separately.But, in electrode system according to the present invention,, a plurality of identical measurement electrode do not having under the situation of statistical analysis even also can being arranged in the parallel circuit with public triggering, and current signal can increase and signal to noise ratio can be improved.Particularly when corresponding measurement electrode was measured at the lower limit place of its measuring range, this was favourable, because the analyte concentration that will measure is low more, signal to noise ratio is generally more unfavorable.
If do not adopt a plurality of identical measurement electrode because of the terseness of design, preferably the zone of the measurement electrode with lower measurement sensitivity is chosen to then that more the zone of the measurement electrode of high measurement sensitivity is bigger than having (next one), is preferably at least greater than 50%.Even under lower measurement sensitivity, this also allows the current signal that obtains to increase and therefore improves signal to noise ratio.
Description of drawings
The example embodiment of middle expression illustrates in greater detail the present invention with reference to the accompanying drawings below.Particularity as herein described can separately or be used in combination to form further improvement.Equate or equivalent elements is identified by the Reference numeral of unanimity.Accompanying drawing comprises:
Fig. 1 is that the flow chart of determining analyte concentration according to electrode system of the present invention is adopted in explanation;
Fig. 2 has illustrated an example embodiment according to electrode system of the present invention;
Fig. 3 has illustrated another example embodiment according to electrode system of the present invention;
Fig. 4 is the sectional view of explanation electrode system shown in Figure 3;
Fig. 5 has illustrated the characteristic example according to first measurement electrode of electrode system of the present invention;
Fig. 6 has illustrated the characteristic example according to second measurement electrode of electrode system of the present invention; And
Fig. 7 is that explanation is used to adopt electrode system according to the present invention to come the schematic diagram of the apparatus in accordance with the present invention of Measurement and analysis substrate concentration.
The specific embodiment
Glucose was its concentration in patient's blood and other body fluid in one day may be through an important example of the analyte of the acute variation between 40mg/dl and the 450mg/dl.For this reason, the measurement that will adopt the concentration of glucose in blood or the tissue fluid below illustrates determining of analyte concentration as the example of the unrestricted scope of the invention.
Fig. 1 is that explanation adopts the implantable electrode system that comprises two electric isolation measurement electrodes with different sensitivity to determine the flow chart of concentration of glucose.First measurement electrode has the first measurement sensitivity of having carried out optimizing from first concentration range of the analyte of 80mg/dl to 500mg/dl at scope.Second measurement electrode has the second measurement sensitivity of having carried out optimizing from second concentration range of the analyte of 20mg/dl to 80mg/dl at scope.Therefore, first concentration range is different from second concentration range.Preferably allow the upper limit of concentration range differ 2 times at least.
Measurement electrode provides its amplitude to depend near the measuring-signal of the current forms of the analyte concentration that measurement electrode is separately.For each measurement electrode, can describe as the electric current I of measuring-signal and the relation between the corresponding analyte concentration C by the characteristic curve that sensitivity parameter characterizes.
In order to determine analyte concentration, the measuring-signal of first measurement electrode is analyzed by characteristic curve 20, and the value C of reflection analyte concentration
FIn first operating procedure 10, determine.In next procedure 30, check the determined value of measuring-signal C by first measurement electrode
FWhether belong to the optimised concentration range of measurement sensitivity of first measurement electrode for this reason.In described example embodiment, optimize first measurement electrode at the analyte concentration that surpasses 80mg/dl.If value C
FTherefore be confirmed as belonging to first concentration range, promptly surpass 80mg/dl, then be worth C
FOutput as a result of.
If by the determined concentration value C of first measurement electrode
FSlight in 80mg/dl, then analyze the measuring-signal of second measurement electrode by the characteristic curve 40 of second measurement electrode.
Preferably, the characteristic curve 40 of second measurement electrode has the slope of possibility steepest so that produce high as far as possible signal to noise ratio for low concentration at the lower concentration values place.Owing to may be restricted as the maximum current of measuring-signal, therefore, saturation effect causes constant or constant in fact maximum current I at the higher concentration place
LimOn the contrary, the characteristic curve 20 of first measurement electrode have near linear shape so that under not from the interferential situation of saturation effect in addition the high analyte substrate concentration also can be determined reliably.Yet, become difficult for analysis by disadvantageous signal to noise ratio by first characteristic curve 20 with the corresponding low measurement electric current I of low concentration, surpass threshold value I
LimThe measurement electric current I can't reasonably analyze by second characteristic curve 40 because of saturation effect.
For this reason, in operating procedure 50, check whether the measurement electric current I of second measurement electrode is lower than given threshold value I
LimIf situation is such, then by analyzing the resulting concentration value C of measuring-signal of second measurement electrode
HThan passing through the determined concentration value C of first measurement electrode
FMore reliable so that concentration value C
HOutput as a result of.But, if the measurement electric current I of second measurement electrode is greater than or equal to threshold value I
Lim, then by the determined concentration value C of first measurement electrode
FThan passing through the determined concentration value C of second measurement electrode
HMore reliable so that value C
FExport as concentration value.
Substantially, if through suitably selection, then operating procedure 50 is dispensable for the value of being checked in operating procedure 30 (being 80mg/dl in the example shown).
But, after electrode system is implanted, may occur each measurement electrode measurement sensitivity variation so that the saturation range of second measurement electrode from low concentration.This situation can be discerned in operating procedure 50, and wherein adopts first measurement electrode to determine that the concentration range of analyte concentration can expand to slightly at where applicable to comprise lower analyte concentration.Same feasible be for this reason the optimised concentration range of first measurement electrode and for this reason the optimised concentration range of second measurement electrode be chosen as overlapping and by determine the analyte concentration in the overlapping region from the statistical analysis of the analysis result of the analysis result of first measurement electrode and second measurement electrode.For example the overlapping region may be selected to the scope of 70mg/dl to 100mg/dl.The noise that can consider each self-corresponding measuring-signal recently selects to be used for the statistical weight that the result to first and second measurement electrode of overlapping region is weighted.
Fig. 2 has illustrated an example embodiment of the electrode system 1 that can be used to carry out described method.Electrode system 1 comprises first measurement electrode 2 and second measurement electrode 3 that has different measuring sensitivity separately.Common counter electrode 4 is associated with two measurement electrode 2,3, and it is in earth potential in operation so that the first measurement electric current I 1 flows between first measurement electrode 2 and antielectrode 4, and the second measurement electric current I 2 flows between second measurement electrode 3 and antielectrode 4.Electrode system 1 also is included as the reference electrode 5 that measurement electrode 2,3 provides reference potential.Reference potential preferably defines by silver/silver chloride redox reaction, although obviously, other redox reaction also can be used for reference electrode.
Substantially, exempt independently reference electrode 5 and also be feasible as reference electrode to antielectrode 4.But, the antielectrode 4 because measurement electric current I 1 and I2 flow through, therefore, the service life that this can make the redox reaction (for example silver/silver chloride) of definition reference potential finally limit electrode system with ceasing to have effect.Adopt independently reference electrode 5, can under mobile situation, provide reference potential without any electric current so that the service life of electrode system unrestricted in this regard.
Fig. 3 has illustrated another example embodiment of implantable electrode system 1, and except the shape of each electrode and arranging, the difference of it and example embodiment shown in Figure 2 also is to provide three measurement electrode 2,3,7 altogether.Similar to electrode system 1 shown in Figure 2, second measurement electrode 3 is used to measure the concentration of glucose less than 80mg/dl.First measurement electrode 2 then is used for the whole concentration range that example embodiment shown in Figure 2 is higher than 80mg/dl, and the 3rd measurement electrode that is used for surpassing the concentration of 300mg/dl is arranged on electrode system shown in Figure 31.
Specifically at the use of two above measurement electrode, the measurement sensitivity of advantageously selecting each measurement electrode is so that the measuring range that they overlap.For example, if optimised second concentration range of optimised first concentration range of the measurement sensitivity of first measurement electrode 2 and the measurement sensitivity of second measurement electrode 3 for this reason is overlapping for this reason, then the test of the likelihood in the overlapping region becomes feasible.In addition, the analyte concentration in the one or several overlapping regions can be determined by the statistical analysis from the analysis result of each measurement electrode.
Fig. 4 is the cross section of explanation electrode system 1 shown in Figure 3, and hatching runs through measurement electrode 2,3 and 7 in view of the above.Electrode 2,3,4,5 and 7 is disposed in preferably on the common carrier of being made by plastic material (as polyimides) 8, and by printed conductor 6 contacts, wherein electrode system 1 can be connected to the analytic unit (not shown) via printed conductor 6.In operation, analytic unit is set to for example predetermined value of 350mV to the current potential of measurement electrode 2,3,7 with respect to reference electrode 5.Though measurement electrode is for example drifted about by the earth potential of depositing proteins after implanting with respect to antielectrode 4, but this allows to produce the defined condition that is used for accurate analysis to measure electric current, because measurement electrode 2,3,7 and reference electrode 5 can be considered to pass through identical drift effect.
The different measuring sensitivity of measurement electrode 2,3,7 preferably at least one of measurement electrode 2,3,7 of the cover layer 11 by comprising the diffusional resistance that produces analyte produces, and the difference between measurement electrode 2,3 and 7 the measurement sensitivity realizes by revising diffusional resistance in view of the above.Because the diffusional resistance of cover layer 11 is big more, each self-corresponding cover layer 11 is just thick more, therefore can realize different diffusional resistances by the different cover layer 11 of thickness easy as can.
For example, for this purpose, the covering barrier film that thickness is 30 μ m, made by bad expanded polymer (as polyurethane) can be coated on first measurement electrode 2, and be manufactured from the same material, covering barrier film that thickness only is 10 μ m can be coated on second measurement electrode 3.Because the tectal diffusional resistance difference of measurement electrode 2,3, the glucose molecule of varying number arrive the enzyme layer of measurement electrode 2,3 at time per unit.The glucoseoxidase of being stored in the enzyme layer makes the glucose molecule degraded so that charge carrier is released, and they are detected and so formation measurement electric current I 1 and I2 on measurement electrode 2,3.In the simplest situation, different diffusional resistances can be realized by the tectal difference in thickness of measurement electrode 2,3.
Another selection provides the difference (for example their porous) in the tectal microstructure or makes cover layer by different materials.For example, the impervious relatively silicone of glucose molecule can be used for the cover layer 11 of the measurement electrode 7 of high concentration, and the permeable relatively polyurethane of glucose molecule can be used for the cover layer 11 of the measurement electrode 3 of intermediate concentration, and can exempt cover layer in the situation of measurement electrode 2.
Bad expanded polymer (as polyurethane) is very favourable for cover layer 11.Cover membranous thickness preferably less than 50 μ m, particularly preferably be that 10 μ m are to 30 μ m.
Because the diffusional resistance difference of the cover layer 11 of measurement electrode 2,3, the glucose molecule of varying number arrive the enzyme layer of measurement electrode 2,3 at time per unit.The glucoseoxidase of being stored in the enzyme layer makes glucose molecule degraded so that charge carrier is released, and they are detected and therefore form different measurement electric currents on measurement electrode 2,3.
Another selection that realizes the different measuring sensitivity of first and second measurement electrode 2,3 is to adopt different enzyme layers 9.For example, in order to increase the measurement sensitivity of first measurement electrode 2, the quantity of enzyme may be selected to be the twice height of the enzyme layer 9 that is second measurement electrode 3 in the enzyme layer 9.
For the electrode system 1 of above-mentioned operate as normal, importantly, all measurement electrode 2,3,7 stand identical analyte concentration.Therefore, each measurement electrode 2,3,7 is preferably separated less than 1.5mm, preferably less than 1mm, particularly preferably less than 700 μ m mutually.If adopt a plurality of measurement electrode, thereby need guarantee distance between electrodes even each other farthest distance can be not excessive.For example, can realize homogenizing analyte concentration in the zone of electrode system 1 by abundant thick dialyzer.Therefore, the thickness of film dialyzer be preferably 50 μ m to 500 μ m, particularly preferably be that 100 μ m are to 300 μ m.
Another selection that is used for making the analyte concentration in the zone of electrode system 1 to homogenize is directly dialyzer not to be arranged in measurement electrode 2,3,7, but measurement electrode 2,3,7 is arranged in the cell by the dialyzer sealing.Such cell for example can be by realizing in the suitable groove that measurement electrode 2,3,7 is arranged in carrier 8 and with dialyzer 12 covering grooves.The height of such cell, promptly the distance from the surface (or their cover layer 11) of measurement electrode 2,3,7 to the bottom side of dialyzer 12 is preferably less than 400 μ m, particularly preferably is less than 300 μ m.
Similar to thick dialyzer, such cell is favourable, because it has served as the container of analyte so that can smoothly fall the instantaneous horizontal obstruction of dialyzer 12.
Fig. 5 understands previous at the characteristic curve 20 described in the context of Fig. 1 in more detail, and described in view of the above characteristic curve represents to represent the electric current I of measuring-signal of first measurement electrode 2 and the functional dependency of analyte concentration C.In actual applications, determine that the certainty of measurement of high analyte substrate concentration is subjected to the restriction of saturation effect.In order to optimize the measurement sensitivity of first measurement electrode that is used for the high analyte substrate concentration, therefore advantageously on whole physiology related concentrations scope, make great efforts to make characteristic shape as much as possible near linear.
In fact the concentration of glucose that surpasses 450mg/dl will never occur in human body so that the shape of the characteristic lines that are higher than 450mg/dl shown in Figure 5 is incoherent.If have linear relationship between electric current I and concentration C, then the sensitivity of measurement electrode can be characterized by single sensitivity parameter, described parameter wherein be with respect to concentration characteristic derivative, be slope.In actual applications, linear relationship can't be realized usually so that need the additional sensitivity parameter so that describe the shape of characteristic lines fully.
As far as possible little for the influence that makes saturation effect, in the sensitivity of first measurement electrode 2 at 450mg/dl place should be at least the 100mg/dl place sensitivity 80%, characteristic situation for example shown in Figure 5.In addition, the sensitivity at the 100mg/dl place should be that 0.1nA/mg/dl is so that can be detected under fully high signal to noise ratio above the concentration of 100mg/dl at least.For the concentration less than about 100mg/dl, characteristic lines shown in Figure 5 cause more and more disadvantageous signal to noise ratio so that the certainty of measurement of low concentration is insufficient.
For this reason, second measurement electrode that has obviously higher sensitivity in this low strength range is used to measure the analyte concentration less than 80mg/dl.An example of the characteristic lines of suitable measurement electrode as shown in Figure 6.In order to make measurement sensitivity high as far as possible at the low concentration place, characteristic curve must be steep as far as possible in the respective concentration scope.Because adopt the available measurement electric current of implant electrode to be restricted, therefore, the high measurement sensitivity at low concentration place is associated with the saturated of higher concentration place.This is tangible from the characteristic significantly smooth of concentration that surpass 200mg/dl in Fig. 6.Opposite with the extremely favourable signal to noise ratio at low concentration place, this causes the extremely disadvantageous signal to noise ratio in high concentration place.
Differ at least 2 times, be preferably at least 3 times in first measurement electrode at the concentration of glucose place of reference concentration, for example 100mg/dl and the measurement sensitivity of second measurement electrode.Preferably, the concentration that belongs to first or second concentration range is selected as reference concentration, for example the arithmetic mean of instantaneous value of the upper and lower bound of one of concentration range.In this context, measuring sensitivity is the derivative of the intensity of measuring-signal with respect to concentration, i.e. the characteristic slope at respective concentration place.
Detect reliably for the critical concentration of glucose that makes 50mg/dl adopts second measurement electrode, the sensitivity of second measurement electrode between 10mg/dl and 100mg/dl should be at least 1mA/mg/dl.This critical concentration of glucose place at 50mg/dl causes the electric current of 50nA at least so that can obtain 5 or better signal to noise ratio.
Fig. 7 is the schematic diagram of the apparatus in accordance with the present invention that explanation adopts electrode system 1 according to the present invention to come the Measurement and analysis substrate concentration.In this context, the analytic unit 23 that provides as microprocessor is provided above-mentioned electrode system 1, and comprises the memorizer of at least one second sensitivity parameter of at least one first sensitivity parameter of wherein having stored the measurement sensitivity that characterizes first measurement electrode 2 and the measurement sensitivity that characterizes second measurement electrode 3.By at least one measuring-signal of one of analytical measurement electrode 2,3, analytic unit 23 determines which concentration range near the analyte concentration the electrode system 1 is in.If analyte concentration belongs to the optimised concentration range of measurement sensitivity of first measurement electrode 2 for this reason, then determine analyte concentration by the measuring-signal of analyzing first measurement electrode 2.If analyte concentration belongs to the optimised concentration range of measurement sensitivity of second measurement electrode 3 for this reason, then determine analyte concentration by the measuring-signal of analyzing second measurement electrode 3.
If the concentration range of each measurement electrode 2,3 is overlapping, the analyte concentration that then belongs to the overlapping region also can be determined by the measuring-signal of analyzing two measurement electrode 2,3.
Maximum in the implantable electrode system is measured electric current and is restricted fully, produces because measure the enzymatic degradation of the required charge carrier of electric current by analyte.Therefore, owing to measure the influence of electric current and employed enzyme, be in depleted risk with near the analyte concentration measuring relevant electrode system 1, particularly the bodily tissue around measurement electrode 2,3 is by body fluid under the dabbling relatively poorly situation, and perhaps near the transmission of the analyte molecule measurement electrode 2,3 is owing to other reason, for example because of obstruction under the forbidden situation.The quantity of the analyte that is consumed by the measurement electrode per minute usually in continuous measurement operation is in the picomole scope, and is promptly smaller.Yet the loss of the analyte concentration in the zone of measurement electrode 2,3 may cause incorrect measurement.In worst situation, this effect may cause the physiology likelihood in the signal intensity to reduce, and promptly pretends the reduction of patient's the intravital analyte concentration of whole body.
Equipment shown in Figure 7 can be used to check that adopting the reduction of electrode system 1 observed concentration of glucose in certain time period is to have natural cause and therefore occur near still only local appearance electrode system in the whole body the patient.By alternant way measuring voltage being put on measurement electrode 2,3 for the non-physiological action by near the reduction of the caused signal intensity of local loss of the concentration of glucose the measurement electrode 2,3 discerns.If measurement electrode 2,3 switches on and off in the period of the some minutes relevant with the detection of loss independently of each other, then can distribute to each measurement electrode test signal separately.If during the course, compare with having the low measurement electrode of measuring sensitivity, detect the rapider reduction of signal intensity for having the measurement electrode of high measurement sensitivity more, then it is the sign that exhausts.
Simple algorithm (for example linear compensation calculate or nonlinear curve analysis) allows to determine that characteristic signals reduces the time for the measurement electric current of measurement electrode 2,3 each, can carry out numerical value and regulates if set up isostatic words in view of the above.If during the course, analytic unit 23 determines that in the period relevant with loss the different qualities signal of measurement electrode 2,3 reduces the time, and then alarm signal can be used to warn the unreliability of the concentration of glucose that is calculated.
As long as therefore the loss of determining does not surpass threshold limit value, then have the selection that numerical compensation is used for determining the measurement function of current loss of the analyte concentration of the analysis of the measurement electric current of real analyte concentration in patient's body.For example, can describe by naive model with respect to the consumption of power of the charge carrier of analyte.Analytic unit 23 can compare with the theoretical value of model based on the determined signal of the current measurement time of reducing, and therefore provided the basis by the numerical compensation of the determined partial analysis substrate concentration of measured value.
Therefore, shown in example embodiment in, analytic unit 23 is carried out processing procedure during the analysis to measure signal.In this process, consideration reduces relevant correction data with the part of the measurement function of current of analyte concentration, in view of the above, in order to obtain correction data, be applied to measuring voltage on the measurement electrode 2,3 and be switched on separately and disconnect and specifically the time of the characteristic signals reduction time analysis to measure electric current by determining to measure electric current distributes.In the simplest situation, this correction data may be that characteristic signals reduces the time.
In example embodiment shown in Figure 7, microprocessor 23 provides the analytic unit that is used for the analysis to measure signal and has allowed to switch on and off separately the control unit that is applied to the corresponding measuring voltage on the measurement electrode 2,3.Analytic unit 23 be designed so that measuring voltage be switched on after at least one the part of the caused analyte concentration of measurement electric current of measurement electrode 2,3 reduce and to be identified and to be used for determining that the analysis of human body or the intravital analyte concentration of animal takes in.This can be by determining to take in current by means of the signal indicating analyte concentration.Another selection is that the part of quantitatively check and analysis substrate concentration reduces, and when calculating the intravital analyte concentration of patient it is carried out numerical compensation.
For example, analyze and control unit 23 also can be used for controlling artificial pancreas or can be connected to the analyte concentration that is used for showing so is determined and/or warn the patient about needing the display device of the high of the precautionary measures or extremely low analyte concentration by proper signal (as acoustical signal).In this context, very advantageously wirelessly (for example by infrared interface or pass through ultrasound wave) with transfer of data to display device.
Claims (11)
1. implantable electrode system that is used to measure human body or the intravital analyte concentration of animal comprises:
Be used for determining first measurement electrode and second measurement electrode of measuring-signal, each relevant information of described analyte concentration self-contained with to be measured of described measuring-signal, in view of the above
Described first measurement electrode has the first measurement sensitivity of first concentration range that is fit to described analyte, and
Described second measurement electrode has the second measurement sensitivity of second concentration range that is different from the described first measurement sensitivity and is fit to described analyte.
2. electrode system as claimed in claim 1 is characterized in that, the measurement sensitivity of described first measurement electrode and described second measurement electrode differs at least 2 times at the reference concentration place.
3. as the described electrode system of any one claim of front, it is characterized in that, each self-contained enzyme layer with enzyme of described first measurement electrode and described second measurement electrode, described enzyme catalyzed conversion by described analyte produces and is captured so that produce the charge carrier of described measuring-signal.
4. electrode system as claimed in claim 3 is characterized in that, the different enzyme layers of the quantity of the described different measuring sensitivity of described first measurement electrode and described second measurement electrode by having different enzymes and/or different enzyme are realized.
5. electrode system as claimed in claim 1 or 2, it is characterized in that, at least one of described first measurement electrode and described second measurement electrode comprises the cover layer of generation to the diffusional resistance of described analyte, and the difference between the described measurement sensitivity of described in view of the above first measurement electrode and described second measurement electrode realizes by revising described diffusional resistance.
6. electrode system as claimed in claim 1 or 2 is characterized in that, described first measurement electrode and described second measurement electrode have common counter electrode.
7. electrode system as claimed in claim 1 or 2 is characterized in that, it comprises another measurement electrode at least, and its measurement sensitivity is fit to another concentration range of described analyte.
8. equipment that is used to measure human body or the intravital analyte concentration of animal comprises:
As the described implantable electrode system of any one claim of front,
Analytic unit is connected to described electrode system, is used to analyze the measuring-signal of described first measurement electrode and described second measurement electrode, and
Memorizer, at least one second sensitivity parameter of wherein having stored at least one first sensitivity parameter of the described measurement sensitivity that characterizes described first measurement electrode and having characterized the described measurement sensitivity of described second measurement electrode,
Described in view of the above analytic unit is designed to allow definite described analyte concentration to belong to which concentration range so that analyze the step of at least one measuring-signal of one of described first measurement electrode and described second measurement electrode, and
If described analyte concentration belongs to described first concentration range, then analyze the described measuring-signal of described first measurement electrode so that determine described analyte concentration by described first sensitivity parameter, and
If described analyte concentration belongs to described second concentration range, then analyze the described measuring-signal of described second measurement electrode so that determine described analyte concentration by described second sensitivity parameter.
9. equipment as claimed in claim 8 is characterized in that, optimised described second concentration range of described first concentration range that described first measurement electrode is optimised and described for this reason second measurement electrode is overlapping in the overlapping region, and
Described analytic unit is designed the one or several described concentration range under so that the described measuring-signal of the described measuring-signal of described first measurement electrode and described second measurement electrode is analyzed separately definite described analyte concentration, and the analyte concentration in the overlapping region is determined by the statistical analysis from the analysis result of the analysis result of described first measurement electrode and described second measurement electrode.
10. equipment as claimed in claim 8 or 9 it is characterized in that described first measurement electrode is connected to first potentiostat, and described second measurement electrode is connected to second potentiostat.
11. equipment as claimed in claim 8 or 9, it is characterized in that, the measuring voltage that is applied on described first measurement electrode and described second measurement electrode switches on and off separately by control unit, described in view of the above analytic unit be designed so that after described measuring voltage is switched at least one the part of the caused described analyte concentration of measurement electric current of described first measurement electrode and described second measurement electrode reduce and be identified, and be used for determining that the described analysis of human body or the intravital described analyte concentration of animal takes in, and carrying out numerical compensation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05024760A EP1785085A1 (en) | 2005-11-12 | 2005-11-12 | Implantable electrode system, method and device for measuring the concentration of an analyte in a human or animal body |
| EP05024760.0 | 2005-11-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1961821A CN1961821A (en) | 2007-05-16 |
| CN100475132C true CN100475132C (en) | 2009-04-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101484619A Active CN100475132C (en) | 2005-11-12 | 2006-11-10 | Implantable electrode system, method and device for measuring the concentration of an analyte in a human or animal body |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20070151868A1 (en) |
| EP (2) | EP1785085A1 (en) |
| JP (1) | JP2007130482A (en) |
| CN (1) | CN100475132C (en) |
| CA (1) | CA2567434A1 (en) |
| HK (1) | HK1104773A1 (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190357827A1 (en) | 2003-08-01 | 2019-11-28 | Dexcom, Inc. | Analyte sensor |
| US8423114B2 (en) | 2006-10-04 | 2013-04-16 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
| US11633133B2 (en) | 2003-12-05 | 2023-04-25 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
| EP1711790B1 (en) | 2003-12-05 | 2010-09-08 | DexCom, Inc. | Calibration techniques for a continuous analyte sensor |
| US8364231B2 (en) | 2006-10-04 | 2013-01-29 | Dexcom, Inc. | Analyte sensor |
| US8532730B2 (en) | 2006-10-04 | 2013-09-10 | Dexcom, Inc. | Analyte sensor |
| EP2069772B1 (en) | 2006-10-04 | 2014-05-21 | DexCom, Inc. | Dual electrode system for a continuous analyte sensor |
| JP5164656B2 (en) * | 2008-04-25 | 2013-03-21 | 株式会社船井電機新応用技術研究所 | Sensor and biosensor |
| JP5378719B2 (en) * | 2008-07-08 | 2013-12-25 | 株式会社船井電機新応用技術研究所 | Sensor system |
| EP2163190A1 (en) * | 2008-09-11 | 2010-03-17 | Roche Diagnostics GmbH | Electrode system for measurement of an analyte concentration in-vivo |
| MX2011008678A (en) * | 2009-02-17 | 2011-09-08 | Siemens Ag | Diagnostic device. |
| US20110027458A1 (en) * | 2009-07-02 | 2011-02-03 | Dexcom, Inc. | Continuous analyte sensors and methods of making same |
| WO2012142502A2 (en) | 2011-04-15 | 2012-10-18 | Dexcom Inc. | Advanced analyte sensor calibration and error detection |
| WO2013016573A1 (en) | 2011-07-26 | 2013-01-31 | Glysens Incorporated | Tissue implantable sensor with hermetically sealed housing |
| US9357958B2 (en) | 2012-06-08 | 2016-06-07 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| US10660550B2 (en) | 2015-12-29 | 2020-05-26 | Glysens Incorporated | Implantable sensor apparatus and methods |
| US10561353B2 (en) | 2016-06-01 | 2020-02-18 | Glysens Incorporated | Biocompatible implantable sensor apparatus and methods |
| US9743871B2 (en) * | 2012-09-24 | 2017-08-29 | Dexcom, Inc. | Multiple electrode system for a continuous analyte sensor, and related methods |
| JP5350531B2 (en) * | 2012-12-18 | 2013-11-27 | 株式会社船井電機新応用技術研究所 | Sensor |
| US10638962B2 (en) | 2016-06-29 | 2020-05-05 | Glysens Incorporated | Bio-adaptable implantable sensor apparatus and methods |
| US20190231236A1 (en) * | 2016-09-21 | 2019-08-01 | University Of Cincinnati | Accurate enzymatic sensing of sweat analytes |
| US10638979B2 (en) | 2017-07-10 | 2020-05-05 | Glysens Incorporated | Analyte sensor data evaluation and error reduction apparatus and methods |
| US11278668B2 (en) | 2017-12-22 | 2022-03-22 | Glysens Incorporated | Analyte sensor and medicant delivery data evaluation and error reduction apparatus and methods |
| US11255839B2 (en) | 2018-01-04 | 2022-02-22 | Glysens Incorporated | Apparatus and methods for analyte sensor mismatch correction |
| WO2021172564A1 (en) * | 2020-02-28 | 2021-09-02 | Ｐｈｃホールディングス株式会社 | Sensor and manufacturing method therefor |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4484987A (en) * | 1983-05-19 | 1984-11-27 | The Regents Of The University Of California | Method and membrane applicable to implantable sensor |
| US4655880A (en) * | 1983-08-01 | 1987-04-07 | Case Western Reserve University | Apparatus and method for sensing species, substances and substrates using oxidase |
| US6175752B1 (en) * | 1998-04-30 | 2001-01-16 | Therasense, Inc. | Analyte monitoring device and methods of use |
| WO2000078992A2 (en) * | 1999-06-18 | 2000-12-28 | Therasense, Inc. | Mass transport limited in vivo analyte sensor |
| WO2002064027A2 (en) * | 2001-02-15 | 2002-08-22 | The Regents Of The University Of California | Membrane and electrode structure for implantable sensor |
| US7011630B2 (en) * | 2001-06-22 | 2006-03-14 | Animas Technologies, Llc | Methods for computing rolling analyte measurement values, microprocessors comprising programming to control performance of the methods, and analyte monitoring devices employing the methods |
| US20030032874A1 (en) * | 2001-07-27 | 2003-02-13 | Dexcom, Inc. | Sensor head for use with implantable devices |
| JP3946516B2 (en) | 2001-12-27 | 2007-07-18 | 株式会社ニシトモ | Biological information measuring device and biological information measuring sensor |
| US9795334B2 (en) * | 2002-04-19 | 2017-10-24 | Sanofi-Aventis Deutschland Gmbh | Method and apparatus for penetrating tissue |
| US7964390B2 (en) * | 2002-10-11 | 2011-06-21 | Case Western Reserve University | Sensor system |
| US7248912B2 (en) * | 2002-10-31 | 2007-07-24 | The Regents Of The University Of California | Tissue implantable sensors for measurement of blood solutes |
| EP1562470A4 (en) | 2002-11-01 | 2009-01-14 | Pelikan Technologies Inc | Method and apparatus for body fluid sampling |
| US20050051427A1 (en) * | 2003-07-23 | 2005-03-10 | Brauker James H. | Rolled electrode array and its method for manufacture |
| US8086323B2 (en) * | 2003-09-23 | 2011-12-27 | Medtronic Minimed, Inc. | Implantable multi-parameter sensing system and method |
| ATE464834T1 (en) * | 2003-09-30 | 2010-05-15 | Hoffmann La Roche | SENSOR WITH IMPROVED BIOCOMPATIBILITY |
| EP1711790B1 (en) * | 2003-12-05 | 2010-09-08 | DexCom, Inc. | Calibration techniques for a continuous analyte sensor |
-
2005
- 2005-11-12 EP EP05024760A patent/EP1785085A1/en not_active Withdrawn
-
2006
- 2006-10-14 EP EP06021578.7A patent/EP1785086B1/en active Active
- 2006-11-07 CA CA002567434A patent/CA2567434A1/en not_active Abandoned
- 2006-11-10 JP JP2006305412A patent/JP2007130482A/en active Pending
- 2006-11-10 CN CNB2006101484619A patent/CN100475132C/en active Active
- 2006-11-12 US US11/558,933 patent/US20070151868A1/en not_active Abandoned
-
2007
- 2007-09-13 HK HK07109972.6A patent/HK1104773A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1785086A3 (en) | 2009-01-28 |
| JP2007130482A (en) | 2007-05-31 |
| US20070151868A1 (en) | 2007-07-05 |
| EP1785086A2 (en) | 2007-05-16 |
| CA2567434A1 (en) | 2007-05-12 |
| CN1961821A (en) | 2007-05-16 |
| HK1104773A1 (en) | 2008-01-25 |
| EP1785086B1 (en) | 2018-05-30 |
| EP1785085A1 (en) | 2007-05-16 |
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